To evaluate the role of high affinity 3H-imipramine binding sites located on the 5-HT axons in the down regulation of Beta-adrenergic receptors in CNS, a selective lesion of the 5-HT axon terminals obtained by an i.c.v. injection of 5,7-dihydroxytryptamine (5,7-DHT) was carried out. This 5,7-DHT lesion prevents the loss of Beta-adrenergic receptor recognition sites and the attenuation of the isoproterenol-sensitive adenylate cyclase activity or of the cAMP accumulation measured in cortical membranes or minces of rats treated repeatedly with imipramine or desipramine. These results suggest that a neuronal loop connecting 5-HT axons with NE synapses participates in the down regulation of NE-receptor function and perhaps in the antidepressant action of imipramine and its congeners. The Vmax of 5-HT uptake by hippocampal minces is increased when the number of 3H-imipramine binding sites to hippocampal membranes is decreased after chronic imipramine and desipramine. Also the inhibitory effect on the 5-HT uptake by various imipramine concentrations "in vitro" is attenuated. Thus an endogenous effector of the 3H-imipramine binding sites may play a physiological role in the regulation of 5-HT uptake. We have partially purified a thermostable nonpeptidic endogenous effector of imipramine binding sites from rat brain which inhibits 5-HT uptake and displaces 3H-imipramine binding. Evidence is available that this endogenous effector is not 5-HT or tryptamine. This effector may be of importance as a biochemical marker to study the action of imipramine and the etiology of certain types of depression. Crude synaptic membranes of rat brain also contain specific high affinity binding sites of an atypical antidepressant, mianserin. The number of 3H-mianserin binding sites is increased following 5,7-DHT lesion, whereas the density of 5-HT2 recognition sites labelled by 3H-ketanserin is unchanged. Repeated daily injections with imipramine decrease the number of ketanserin binding sites but not of mianserin binding sites. Thus the mianserin recognition site appears to be a modulatory site distinct from 5-HT2 recognition sites, though both contribute to the function of 5-HT receptor complex. Studies have been undertaken in order to elucidate the molecular mechanisms underlying the Beta-receptor down-regulation elicited by repeated treatments with the other atypical antidepressants such as iprindole and bupropion.